The benzoic acid salt of 4xe2x80x3-deoxy-4xe2x80x3-epi-methylamino avermectin B1a/B1b is known and known to be a stable salt as described in European Patent Publication EP 0465121-A1. The added stability relative to the stability of the previously described hydrochloride salt provided much greater shelf life for this important agricultural insecticide.
This invention is concerned with the most stable of four crystalline forms of the benzoic acid salt of 4xe2x80x3-deoxy-4xe2x80x3-epi-methylamino avermectin B1a/B1b a known agricultural insecticide, and processes for preparing it.
The four crystalline forms that have been identified are designated as forms A, B, C and D, three of which are hydrated (B, C and D). The most thermodynamically stable crystalline form is the hemi-hydrate B. Knowing the most stable crystalline form and devising processes for producing the product in that form is extremely important in that it provides bulk material with crystal homogeneity that is not going to transform to another crystal habit on storage.
The novel crystal form B has been found to be significantly less hygroscopic than the other crystal forms and in addition it retains much less solvent. These attributes provide for a much more stable and uniform form of the final product which is used to prepare agricultural products and pharmaceutical dosage forms.
The novel processes for producing crystal form B comprises crystallization of the compound from an organic solvent containing a controlled amount of water.
The novel compound of this invention is crystalline 4xe2x80x3-deoxy-4xe2x80x3-epi-methylamino avermectin B1a/B1b, benzoic acid salt, hemihydrate in substantially pure form.
It has structural formula: 
wherein R is xe2x80x94CH3 (B1a) or xe2x80x94H (B1b) and is referred to as Crystal form B, Type B or similar designation.
The differential scanning calorimetry (DSC) curve determined at a heating rate of 20xc2x0 C./min. under nitrogen flow in an open cup is characterized by a relatively broad water loss endotherm with a peak temperature of 74xc2x0 C. and a major melting/decomposition endotherm with peak temperature of 155xc2x0 C., extrapolated onset temperature of 150xc2x0 C. with an associated heat of 56 Joules/gm. The x-ray powder diffraction pattern for Type B is characterized by d-spacings of 18.13, 9.08, 8.68, 5.03, 4.61, 4.53, 3.97 and 3.82 xc3x85. The aqueous solubility is pH dependent. At pH 5, acetate buffer, it has a solubility of 0.32 mg/ml.
The novel process of this invention comprises recrystallizing the compound in any energetic state from an aqueous organic solvent. Preferably form B is prepared from Form A.
The aqueous organic solvent useful in the novel process is preferably acetonitrile with 2-4% w/w of water; methyl t-butyl ether (MTBE) with 0.5 to 0.8% w/w of water; or isopropanol (IPA) with 0.1-0.3% w/w of water.
Compound of crystal form A, C or D is dissolved in the organic solvent at about 50-60xc2x0 C. treated with the requisite amount of water, seeded with Type B crystals, cooled to and aged at about 15-30xc2x0 C. for about 2-4 hours and further cooled to about 5xc2x0 C. over a period of about 1-2 hours.
The crystalline product is collected on a filter and dried in vacuo.
The utility and methods of use of the benzoic acid salt described herein and the free base thereof are well known by those skilled in the art and fully described in the scientific and patent literature.
It has significant parasiticidal activity as an anthelmintic, ectoparasiticide, insecticide and acaricide, in human and animal health and in agriculture. As an agricultural pesticide it has activity against insect pests of stored grains such as Tribolium sp., Tenebrio sp., and of agricultural plants such as spider mites, (Tetranychus sp.), aphids, (Acyrthiosiphon sp.); against migratory orthopterans such as locusts and immature stages of insects living on plant tissue. The compound is useful as a nematocide for the control of soil nematodes and plant parasites such as Meloidogyne sp. which is of importance in agriculture. The compound is active against other plant pests such as the southern army worm and Mexican bean beetle larvae.
The compounds are applied using known techniques as sprays, dusts, emulsions and the like, to the growing or stored crops to effect protection from such agricultural pests. For the treatment of growing crops, the compound is administered at a rate of about 5-50 gms per hectare. For the protection of stored crops it is normally administered by spraying with a solution containing from 0.1-10 ppm. of the compound.